Increasing PKG activity protects aging kidney from ischemic-reperfusion induced injury

Aging is associated with increased incidence of acute kidney injury (AKI). This age-dependent increase in susceptibility to AKI is linked to a decreased renal functional recovery and even progression to advanced chronic kidney disease, a severe health problem worldwide. Despite advances in our understanding of the cellular and molecular aspects of AKI in recent years, the relationship between aging and AKI remains poorly understood and requires further mechanistic studies. Preliminary studies demonstrated that nitric oxide (NO) and its downstream signaling pathway cGMP and cGMP-dependent protein kinase (PKG) was down-regulated in aging kidney, which was associated with aging-related renal functional changes. Moreover, preliminary data identified a novel inhibitory effect of PKG on tubular cell necrosis and apoptosis following renal ischemia reperfusion (IR) induced acute kidney injury in young mice and an inhibitory effect of PKG on macrophage migration, suggesting a therapeutic potential of PKG for renal IR injury. In this proposal, we will test the hypothesis that down-regulation of NO/cGMP/PKG signaling in the kidney contributes to increased susceptibility of older individuals to ischemia reperfusion mediated AKI. We will determine whether genetically or pharmacologically increased PKG activity reduces the susceptibility of old animals to ischemia mediated acute kidney injury in Aim 1. The mechanisms of reduced NO/cGMP/PKG signaling in aging kidney will be determined in Aim 2. These studies will establish the significance of PKG in acute kidney injury in aging population. Importantly, utilization of sildenafil (an inhibitor of cGMP specific phosphodiesterase 5 (PDE5)) to increase PKG activity in the proposed studies has a significant clinical relevance. Sildenafil is a drug used to treat erectile dysfunction (ED) and pulmonary arterial hypertension (PAH) in clinic. The current proposed studies will test a novel potential application of sildenafil for AKI in older population. Hopefully, these proposed studies will lead to new therapeutic strategy for acute kidney injury in aging population.